Can cancer be reversed by engineering the tumor microenvironment?

Abstract

To advance cancer research in a transformative way, we must redefine the problem. Although epithelial cancers, such as breast cancer, may be caused by random somatic gene mutations, the reality is that this is only one of many ways to induce tumor formation. Cancers also can be produced in experimental systems in vitro and in vivo, for example, by inducing sustained alterations of extracellular matrix (ECM) structure. Moreover, certain epithelial cancers can be induced to 'reboot' and regenerate normal tissue morphology when combined with embryonic mesenchyme or exogenous ECM scaffolds that are produced through epithelial-stromal interactions. At the same time, work in the field of Mechanical Biology has revealed that many cell behaviors critical for cancer formation (e.g., growth, differentiation, motility, apoptosis) can be controlled by physical interactions between cells and their ECM adhesions that alter the mechanical force balance in the ECM, cell and cytoskeleton. Epithelial tumor progression also can be induced in vitro by changing ECM mechanics or altering cytoskeletal tension generation through manipulation of the Rho GTPase signaling pathway. Mechanical interactions between capillary cells and ECM that are mediated by Rho signaling similarly mediate control of capillary cell growth and angiogenesis, which are equally critical for cancer progression and metastasis. These findings question basic assumptions in the cancer field, and raise the intriguing possibility that cancer may be a reversible disease that results from progressive deregulation of tissue architecture, which leads to physical changes in cells and altered mechanical signaling. This perspective raises the possibility of developing a tissue engineering approach to cancer therapy in which biologically inspired materials that mimic the embryonic microenvironment are used to induce cancers to revert into normal tissues.

Fig. 1. Cancer as an Engineering Problem

A theoretical model for mechanical control of tissue remodeling during normal epithelial development and tumor formation. Left) During normal development, regional increases in ECM turnover result in formation of local defects in the basement membrane (green), which stretches and thins due to the contraction and pulling of neighboring epithelium (white arrows) and underlying mesenchyme (gray arrow). Cells adherent to this region of the basement membrane will distort or experience increased stresses and thus, become preferentially sensitive to growth stimuli. Cell division is paralleled by deposition of new basement membrane (red) and thus, cell mass expansion and ECM extension are tightly coupled; this leads to bud formation in this localized region. Micrographs of normal epithelial bud formation during embryonic lung formation, and corresponding engineering depictions of the local mechanical strain distributions are shown at the far left. Right) During tumor formation in an adult epithelium, basement membrane thinning, changes in cell mechanics, and an increase in the sensitivity of adjacent cells to growth stimuli are also observed, much like during epithelial bud formation (left). But because cell division is not accompanied by basement membrane extension, piling up of epithelial cells and disorganization of normal tissue architecture result. If these changes in tissue structure and mechanics are sustained over time, then this continued growth stimulus could lead to selection of anchorage-independent cells, and development of a malignant carcinoma.

Fig. 2. Mechanical Control of Cell Growth & Function

Left) Diagrammatic side-view and top-view representations of cells adherent to microfabricated circular ECM islands on the micrometer scale that constrain cell spreading are shown at the top. Phase contrast microscopic images of capillary endothelial cells cultured on these micropatterned substrates are displayed at the bottom. The effects of cell spreading (distortion) can be distinguished from those due to ECM contact formation by using many smaller, focal adhesion-sized islands (5 μm) ECM islands that cause the cells to spread from island to island; these cells spread as much as cells on the large island, but contact the total amount of ECM as on the small island. Right) Diagram depicting general effects of cell spreading on the growth, differentiation and apoptosis of epithelial and endothelial cells, when manipulated using the micropatterned substrates shown at left (see refs ???, for details). Note that, in general, cell growth increases with spreading, whereas apoptosis is switched on in round cells, and cells preferentially undergo differentiation in a moderately spread state.

Fig. 3. An Engineering Solution to Cancer?

Left) Diagrams showing how combining epithelial tumor cells with embryonic mesenchyme induces the cancer cells to reverse their phenotype and restore normal tissue morphology. Right) Analogous diagrams describing a potential future form of cancer reversal therapy that utilizes synthetic biomimetic materials, which mimic the inductive behavior of embryonic mesenchyme.